The broad objectives of this proposal are: to achieve better means of cell and tissue protection, and to gain a better understanding of cell-protective actions and functions of the female sex hormone estrogen. Specifically and near-term, we propose to examine the ability of estrogen to protect against certain forms of acute lung injury, and the mechanisms of this action. Specific objectives: 1) Document the protective properties of estrogen hormone against acute lung injury. Hypothesis: Already shown to be cytoprotective in neuronal cells and the cardiovascular system, estrogen is protective in the lung as well. This hypothesis will be tested in three models of injury: a) excitotoxicity, i.e., injury/cell death due to species overstimulation of NMDA receptors; b) oxidative stress, caused by the generation of reactive oxygen species (ROS) by the herbicide paraquat; and c) endotoxin shock, which leads to multi-organ dysfunction. Endpoints will be the speed of onset and the severity of high-permeability pulmonary edema in models a and b, and the survival time and organ damage, in model c. 2) Explore the mechanisms, sites, and pathways of lung protection by estrogen. Hypothesis: Acting at multiple sites, estrogen exerts anti-apoptotic (pro-survival), anti-inflammatory, anti-oxidant, and other beneficial effects. These possible sites and models of protection will be examined in the models of injury named above. We will evaluate: a) the specificity and nature of the effect (i.e., genomic vs. nongenomic); b) relative importance of different receptors (ER-alpha, ER-beta), membrane binding sites, and transduction pathways; c) the contribution of estrogen-induced upregulation of the expression of (VIP), which has known anti-injury and anti-inflammatory properties; d) possible interactions and "transcription cross-talk" between estrogen and retinoic acid receptors, and d) anti-apoptotic and pro-survival activities of estrogen. The proposed work extends recent research on the protective effects of estrogen in the brain and the cardiovascular system. Preliminary data support the validity of the hypotheses underlying this project. This is the first, and probably the only, investigation of the female sex hormone estrogen as a lung-protective agent.